4-Hydroxy-3-(5-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides

ABSTRACT

WHEREIN R1, R2 and R3 are hydrogen or alkyl. These compounds are useful as antiinflammatory agents.   Compounds of the formula:

United States Patent Zinnes et al.

H 3,868,367 Feb. 25, 1975 4-HYDROXY-3-(5- ISOXAZOLYLCARBAMOYL)-2H-1,2- BENZOTHIAZINE 1,1-DIOXIDES [75] Inventors: Harold Zinnes, Rockaway; Martin L. Schwartz, Gillette; Neil A. Lindo, Chatham; John Shavel, Jr., Mendham, all of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

22 Filed: Apr. 11, 1974 [21] Appl. No.: 460,266

[52] U.S. Cl. 260/243 R, 424/246 [51] Int. Cl C07d 93/02 [58] Field of Search 260/243 R [56] References Cited UNITED STATES PATENTS 3,822,258 7/1974 Zinnes et al. 260/243 Primary Examiner-John M. Ford Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow [57] ABSTRACT Compounds of the formula:

wherein R R and R are hydrogen or alkyl. These compounds are useful as antiinflammatory agents.

3 Claims, N0 Drawings 4-HYDROXY-3-(5-ISOXAZOLYLCARBAMOYL)- 2H-l,2-BENZOTHIAZINE 1,1-DIOXIDES The present invention relates to compounds of the formula:

wherein R,, R and R are hydrogen or alkyl.

Alkyl as used herein is meant tobe the residue derived from an aliphatic hydrocarbon having 1 to 7 car- 2 4-Hydroxy-2-methyl'N-(3-methyl-5-isoxazolyl)-2H- 1,2-benzothiazine-3-carboxamide 1,1-Dioxide. A

mixture of 19.8 g (0.07 mol) of 3-carbethoxy-4- hydroxy-Z-methyl-ZH-l ,2-benzthiazine 1,1-dioxide, 7.0 g (0.077 mol) of 5-amino-3-methylisoxazole, and 300 ml of xylene was refluxed for 22 hrs. in a Sox holet apparatus, the thimble of which contained g of Linde 4A molecular sieve. The reaction mixture was allowed to stand atroom temperature and the resulting precipitate was collected to give 16.9 g of material, mp 236 to 246C dec. Recrystallization from 1,4-dioxan gave 11.0 g of product, mp 249 to 254C dec.

Anal. Calcd for C H N O Sz C, 50.14; H, 3.91; N. 12.53; S, 9.56. Found: C, 50.12; H, 4.07; N, 12.42; S,

bon atoms. These include, for example: methyl, ethyl, 9 propyl, isopropyl, butyl, isobutyl and the like.

These compounds also form salts with alkali metals EXAMPLE 2 and alkaline earth metals; these salts are included within the scope of this invention. 6 OH 3 Compounds 1 and their salts are useful as anti- N inflammatory agents. For example, when administered l orally to rats at about 100 mg/kg they are able to cause /NCl-l 0 reduction in swelling of the paw induced by injection 3 into the foot pads of an irritant such as carrageenin.

These compounds are indicated in the-management of conditions such as rheumatoid arthritis. Generally an gt: ;3' 3 i fii 'gg iqgi zggggig i i 'igfiiag g' oral dose of 100 mg/kg 2 or 3 times daily is suggested. enzo n l d 5 7 02 This dose can be varied depending upon the conditions 6 Same proce g h j g d Q h' l 1' 7 of the patient, for example, age, sex and weight of the mol) 9 3'Car F U y rOX)" y patient by methods known to the healing arts benzothlazme 1,1-d1ox1de, 3.4 g (0.03 mol) of 5- For oral administration the compounds of these salts f X P and 150 ml of Xyleneare formulated with diluents such as lactose and then Allowmg the reactloll mlxture to cool to room F P encapsulated i gelatin capsules atur cau sed precipitation of 5.75 g of material, mp According to the present invention these comdec. Recrystallrzatloon from methanol gave pounds are prepared by refluxing an ester of structure g of P p 190 (160- II, where R, is alkyl, with an appropriate Saminoisox- Anal- Calcd for is is a s H N, azole derivative of structure 111 in a solvent such as xy- Foundi lene. 9.34.

O OH COR 2 iw 4 H211 l I so NR O\N/ R3 II III The starting material 11 is prepared as described in US. We claim: Pat. No. 3,501,466. The starting S-amino-isoxazoles l. A compound of the formula: (III) are prepared as described in Chem. Pharm. Bull. Japan 14 1277 (1966) and Brit. Patent 595,775 (1947); C. A. 42 4202 (1948) (Hofmann La Roche). O E R As indicated above, compound 1 forms salts with al- NH 2 kali metals, alkaline earth metals and amines. For example. sodium, potassium, calcium, and triethanol- NR 0 R amine. These are prepared by treating. for example, the 3 parent moiety with sodium, potassium, or a calcium hydroxide. The salts are recovered by conventional techniques.

In order to further illustrate the practice of this invention, the following examples are included:

EXAMPLE 1 wherein R R and R are hydrogen or alkyl of l to 7 carbon atoms and nontoxic pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 which is 4- hydroxy-2-methyl-N-(3-methyl-5-isoxazolyl)-2H-1,2-

5 benzothiazine-3-carboxamide 1,1-Dioxide.

3. A compound according to claim 1 which is N-(3,4- dimethyl-S-isoxazolyl)-4-hydroxy-2-methyl-2H-1,2- benzothiazine-3-carboxamide 1,1-Di0xide. 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 which is 4-hydroxy-2-methyl-N-(3-methyl-5-isoxazolyl)-2H-1,2-benzothiazine-3 -carboxamide 1,1-Dioxide.
 3. A compound according to claim 1 which is N-(3,4-dimethyl-5-isoxazolyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3 -carboxamide 1,1-Dioxide. 